title: Rapamycin induces ILT3(high)ILT4(high) dendritic cells promoting a new immunoregulatory pathway.
abstract: ILT3(high)ILT4(high) dendritic cells (DCs) may cause anergy in CD4(+)CD45RO(+)CD25(+) T cells transforming them into regulatory T cells (Tregs). Here, we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients. Forty renal transplant patients with biopsy-proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction. At conversion and 2 years thereafter, we measured the rapamycin effects on circulating DCs (BDCA1/BDCA2 and ILT3/ILT4 expression), CD4(+)/CD25(high)/Foxp3(+) Tregs, CD8(+)/CD28(-) T cells, and the Th1/Th2 balance in graft biopsies. In rapamycin-treated patients, peripheral BDCA2(+) cells were significantly increased along with ILT3/ILT4(+) DCs. The number of circulating CD4(+)/CD25(high)/Foxp3(+)/CTLA4(+) Tregs, CD8(+)CD28(-) T cells, and HLA-G serum levels were higher in the rapamycin-treated group. The number of ILT3/ILT4(+)BDCA2(+) DC was directly and significantly correlated with circulating Tregs and CD8(+)CD28(-) T cells. ILT3/ILT4 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin-treated patients. Thus, rapamycin induces the upregulation of ILT3 and ILT4 on the DC surface, and this effect is associated with an increase in the number of Tregs and expansion of the CD8(+)CD28(-) T cell population. This suggests that mTOR inhibition may promote a novel immunoregulatory pathway.
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stallone
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Pontrelli
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Infante
authors.affiliation: Department of Medical and Surgical Sciences, Clinical Pathology, University of Foggia, Foggia, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Gigante
authors.affiliation: Department of Medical and Surgical Sciences, Clinical Pathology, University of Foggia, Foggia, Italy.
authors.forename: Giuseppe S
authors.initials: GS
authors.lastname: Netti
authors.affiliation: Department of Medical and Surgical Sciences, Clinical Pathology, University of Foggia, Foggia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ranieri
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
authors.affiliation: Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
mesh_terms: D000328:Adult; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D019737:Transplants / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; C491341:LILRB2 protein, human; C107907:LILRB4 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D020123:Sirolimus